Fracture rate increases after immune checkpoint inhibitor treatment: a potential new immune related adverse event

Ye, Carrie; Lee, Kevin; Leslie, William D.; Lin, Mu; Walker, John; Kolinsky, Michael

doi:10.1007/s00198-023-06690-1

Cited by 5 publications

(4 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The above studies have shown the unique role of BMD in predicting tumor progression. In addition, recent studies and case reports have found that cancer patients have an increased risk of early fractures after starting ICIs, which may be related to reduced bone density and osteoporosis caused by T cell activation ( 23 – 25 ). This suggests that ICIs also promote bone loss and thus affect clinical outcomes, although we did not follow up the changes in BMD after ICI treatment.…”

Section: Discussionmentioning

confidence: 99%

Bone mineral density as an individual prognostic biomarker in NSCLC patients treated with immune checkpoint inhibitors

Lou,

Gong,

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

BackgroundImmune checkpoint inhibitors (ICIs) have left a deep impression in the treatment of non-small cell lung cancer (NSCLC), however, not all patients benefit from it. The purpose of this study was to investigate the prognostic value of baseline bone mineral density (BMD) derived from chest computed tomography (CT) scans in NSCLC patients treated with ICIs.MethodsThis study included patients with advanced NSCLC who underwent ICI treatment at the Wuhan Union Hospital from March 2020 to October 2022. Baseline BMD was evaluated at non-contrast chest CT at the level of first lumbar vertebra. Patients were divided into BMD-lower group and BMD-higher group according to the optimal cutoff value calculated by X-tile software. Baseline characteristics of the two groups were compared and variables between the two groups were balanced by propensity score matching (PSM) analysis. We calculated the objective response rate (ORR) and disease control rate (DCR) of the two groups and analyzed overall survival (OS) and progression-free survival (PFS) using BMD and other clinical indexes through Cox regression models and Kaplan-Meier survival curves.ResultsA total of 479 patients were included in this study, and all patients were divided into BMD-lower group (n=270) and BMD-higher group (n=209). After PSM analysis, each group consisted of 150 patients. ORR (43.3% vs. 43.5% before PSM, P = 0.964; 44.7% vs. 44.7% after PSM, P = 1.000) and DCR (91.1% vs. 94.3% before PSM, P = 0.195; 93.3% vs. 96.7% after PSM, P =0.190) were similar in two groups. There was no statistically significant relationship between BMD degree and PFS before (16.0 months vs. 18.0 months, P = 0.067) and after PSM analysis (17.0 months vs. 19.0 months, P = 0.095). However, lower BMD was associated with shorter OS both before (20.5 months vs. 23.0 months, P< 0.001) and after PSM analysis (20.0 months vs. 23.0 months, P = 0.008).ConclusionLower baseline BMD is associated with worse clinical outcomes in NSCLC patients treated with ICIs. As a reliable and easily obtained individual prognostic biomarker, BMD can become a routine detection indicator before immunotherapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Bone mineral density as an individual prognostic biomarker in NSCLC patients treated with immune checkpoint inhibitors

Lou,

Gong,

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…26 27 38 In contrast, ICIs have been shown to increase bone resorption and thus trigger skeletal adverse events in patients with cancer. [39][40][41] In this study, we investigated the long-term effect of ICIs on levels of bone metabolism biomarkers in patients with cancer and elucidated their impact on bone remodeling using a novel, bioengineered 3D model of the BMU. To the best of our knowledge, our findings highlight for the first time the dual effect of ICIs on bone metabolism through the impaired differentiation of mature OCs, which indirectly leads to increased osteogenesis.…”

Section: Discussionmentioning

confidence: 99%

Favorable impact of PD1/PD-L1 antagonists on bone remodeling: an exploratory prospective clinical study and ex vivo validation

Gassner,

Chittilappilly,

Pirich

et al. 2024

J Immunother Cancer

View full text Add to dashboard Cite

BackgroundSkeletal morbidity in patients with cancer has a major impact on the quality of life, and preserving bone health while improving outcomes is an important goal of modern antitumor treatment strategies. Despite their widespread use in early disease stages, the effects of immune checkpoint inhibitors (ICIs) on the skeleton are still poorly defined. Here, we initiated a comprehensive investigation of the impact of ICIs on bone health by longitudinal assessment of bone turnover markers in patients with cancer and by validation in a novel bioengineered 3D model of bone remodeling.MethodsAn exploratory longitudinal study was conducted to assessserum markers of bone resorption (C-terminal telopeptide, CTX) and formation (procollagen type I N-terminal propeptide, PINP, and osteocalcin, OCN) before each ICI application (programmed cell death 1 (PD1) inhibitor or programmed death-ligand 1 (PD-L1) inhibitor) for 6 months or until disease progression in patients with advanced cancer and no evidence of bone metastases. To validate the in vivo results, we evaluated osteoclast (OC) and osteoblast (OB) differentiation on treatment with ICIs. In addition, their effect on bone remodeling was assessed by immunohistochemistry, confocal microscopy, and proteomics analysis in a dynamic 3D bone model.ResultsDuring the first month of treatment, CTX levels decreased sharply but transiently. In contrast, we observed a delayed increase of serum levels of PINP and OCN after 4 months of therapy. In vitro, ICIs impaired the maturation of preosteoclasts by inhibiting STAT3/NFATc1 signaling but not JNK, ERK, and AKT while lacking any direct effect on osteogenesis. However, using our bioengineered 3D bone model, which enables the simultaneous differentiation of OB and OC precursor cells, we confirmed the uncoupling of the OC/OB activity on exposure to ICIs by demonstrating impaired OC maturation along with increased OB differentiation.ConclusionOur study indicates that the inhibition of the PD1/PD-L1 signaling axis interferes with bone turnover and may exert a protective effect on bone by indirectly promoting osteogenesis.

show abstract

“…Previous literature has reported fracture as a potential risk associated with ICIs treatment. It has been found that the incidence of fractures increases after the initiation of ICIs treatment ( Filippini et al, 2021 ; Ye et al, 2023 ). However, the characteristics of ICIs-induced fractures remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Musculoskeletal adverse events induced by immune checkpoint inhibitors: a large-scale pharmacovigilance study

Liu,

Li,

et al. 2023

Front. Pharmacol.

View full text Add to dashboard Cite

Background: The musculoskeletal toxicity of immune checkpoint inhibitors (ICIs) is receiving increasing attention with clinical experience. Nevertheless, the absence of a systematic investigation into the musculoskeletal toxicity profile of ICIs currently results in the under-recognition of associated adverse events. Further and more comprehensive investigations are warranted to delineate the musculoskeletal toxicity profile of ICIs and characterize these adverse events.Material and methods: The present study employed the FDA Adverse Event Reporting System database to collect adverse events between January 2010 and March 2021. We utilized both the reporting odds ratio and the Bayesian confidence propagation neural network algorithms to identify suspected musculoskeletal adverse events induced by ICIs. Subsequently, the clinical characteristics and comorbidities of the major musculoskeletal adverse events were analyzed. The risk of causing these events with combination therapy versus monotherapy was compared using logistic regression model and Ω shrinkage measure model.Results: The musculoskeletal toxicity induced by ICIs primarily involves muscle tissue, including neuromuscular junctions, fascia, tendons, and tendon sheaths, as well as joints, spine, and bones, including cartilage. The toxicity profile of PD-1/PD-L1 and CTLA-4 inhibitors varies, wherein the PD-1 inhibitor pembrolizumab exhibits a heightened overall risk of inducing musculoskeletal adverse events. The major ICIs-induce musculoskeletal adverse events, encompassing conditions such as myositis, neuromyopathy (including myasthenia gravis, Lambert-Eaton myasthenic syndrome, Guillain-Barré syndrome, and Chronic inflammatory demyelinating polyradiculoneuropathy), arthritis, fractures, myelitis, spinal stenosis, Sjogren’s syndrome, fasciitis, tenosynovitis, rhabdomyolysis, rheumatoid myalgia, and chondrocalcinosis. Our study provides clinical characteristics and comorbidities of the major ICIs-induced musculoskeletal adverse events. Furthermore, the combination therapy of nivolumab and ipilimumab does not result in a statistically significant escalation of the risk associated with the major musculoskeletal adverse events.Conclusion: Immune checkpoint inhibitors administration triggers a range of musculoskeletal adverse events, warranting the optimization of their management during clinical practice.

show abstract

Fracture rate increases after immune checkpoint inhibitor treatment: a potential new immune related adverse event

Cited by 5 publications

References 20 publications

Bone mineral density as an individual prognostic biomarker in NSCLC patients treated with immune checkpoint inhibitors

Bone mineral density as an individual prognostic biomarker in NSCLC patients treated with immune checkpoint inhibitors

Favorable impact of PD1/PD-L1 antagonists on bone remodeling: an exploratory prospective clinical study and ex vivo validation

Musculoskeletal adverse events induced by immune checkpoint inhibitors: a large-scale pharmacovigilance study

Contact Info

Product

Resources

About